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CN110240537A - A kind of indenes fluoroacetic acid class compound and its preparation method and application - Google Patents

A kind of indenes fluoroacetic acid class compound and its preparation method and application Download PDF

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CN110240537A
CN110240537A CN201910430459.8A CN201910430459A CN110240537A CN 110240537 A CN110240537 A CN 110240537A CN 201910430459 A CN201910430459 A CN 201910430459A CN 110240537 A CN110240537 A CN 110240537A
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CN110240537B (en
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陈方
赵东明
张继红
尹洪海
刘晓茜
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Chengdu Achi Biopharmaceutical Technology Co ltd
CHENGDU TIANTAISHAN PHARMACEUTICAL CO LTD
Shanghai Puyuan Medical Technology Center
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CHENGDU TIANTAISHAN PHARMACEUTICAL Co Ltd
Shanghai Puyuan Medical Science And Technology Center
Chengdu Archie Biomedical Technology Co Ltd
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Abstract

The present invention provides compound shown in Formulas I or its conformers or its optical isomer or its pharmaceutically acceptable salt or its pharmaceutically acceptable salt or its prodrug or its hydrate or its solvate.It is experimentally confirmed, the compounds of this invention has higher agonist activity to PPAR α, γ or δ, may be used as PPAR agonist；Furthermore, the compounds of this invention pair a variety of biochemical parameters relevant to liver disorders include that triglycerides, cholesterol etc. have significant front regulating effect, for prepare lipid and/or abnormal carbohydrate metabolism related disease, liver related disease, transaminase the drug of blood plasma level exception related disease provide new selection.

Description

A kind of indenes fluoroacetic acid class compound and its preparation method and application
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of indenes fluoroacetic acid class compound and preparation method thereof and Purposes.
Background technique
Liver is one of mostly important organ of human body and one of the highest organ of onset risk.Non-alcoholic fatty Liver (NAFLD) has become the worldwide first big hepatopathy, can not only be further development of nonalcoholic fatty liver Inflammation (NASH), cirrhosis, hepatocellular carcinoma, it is also closely related with cardiovascular and cerebrovascular disease, therefore it is increasingly subject to related discipline researcher Attention.
Specifically, non-alcohol-induced fatty liver disease (is usually defined by the abnormal delay of lipid in the cell For steatosis) caused by, since liver is mainly responsible for lipid metabolism, the exception of lipid in the cell is trapped in liver In frequently occur.Nonalcoholic fatty liver has Various Tissues form, including hepatic steatosis and is drawn with liver cell destruction The nonalcoholic fatty liver disease that liver inflammation, steatosis, necrosis and the fibre modification risen is characterized.Cause non-alcoholic rouge Fat liver is relevant the reason is that diversified, including diabetes B, obesity, dyslipidemia, metabolic syndrome, uses hepatotoxicity wind agitation Drug, toxin, infectant treatment and other external causes.
Peroxisome proliferation-activated receptors (peroxisome proliferator-activated Receptor, PPAR) it is a kind of nuclear factor by ligand activation, it is divided into PPAR α, β (or δ) and tri- kinds of hypotypes of γ.Liver is thin Born of the same parents great expression PPAR α and a small amount of PPAR δ, PPAR γ.PPAR α passes through to intrahepatic fat acid oxidase and inflammatory reaction related gene The regulation of expression plays a significant role in Liver lipids metabolism and inflammatory reaction, and functional defect can cause liver cell fatty Denaturation, necrosis and inflammatory cell infiltration and lead to nonalcoholic fatty liver.Therefore, PPAR agonist is as treatment non-alcoholic rouge The drug of fat liver has very big prospect.
So far, Liver Fibrosis disease, particularly nonalcoholic fatty liver or non-alcoholic can effectively be treated The method of fatty hepatitis is still very insufficient.For the patient with nonalcoholic steatohepatitis, there is presently no determinations Treatment method, have it is several it is therapeutic selection just in clinical test testing researches.These researchs are related to using many differences The compound (fibrates, thiazolidinediones, biguanides, Statins, Cannabinoids) and therapy target (nuclear receptor, blood of family Angiotensin receptor, Cannabined receptor, HMG-CoA reductase).But research finds that these drugs are improving liver condition feelings While condition, but there is problem in safety, can generate side effect to patient.For example it is related to thiazolidinediones (Roger recently Column ketone and Pioglitazone) studies have shown that these drugs can improve liver condition, but will increase the congested heart of patient simultaneously The risk to decline with osteoporosis can also cause patient's weight to increase.It is related to the clinical test discovery of Cannabinoids administration for another example, The disorder of patients' neural's spirit is caused while treatment.
Therefore, there is an urgent need to develop, one kind can effectively treat liver disease and safety is good, few side effects now Drug.
Summary of the invention
The object of the present invention is to provide a kind of medicines that can effectively treat liver disease and safety is good, tolerance is good Object.
The present invention provides compound shown in Formulas I or its conformer or its optical isomer or its pharmaceutically may be used The salt of receiving or its pharmaceutically acceptable salt or its prodrug or its hydrate or its solvate:
Wherein, R1Selected from hydroxyl, C1-5Alkoxy, C1-5Alkyl；
R3、R4It is each independently selected from H, halogen, C1-5Alkyl, C1-5Alkoxy；
R2Selected from hydrogen, halogen, cyano, hydroxyl, carboxyl ,-NH2、-NO2、By 0~3 R9Substituted C1-5 Alkyl, by 0~3 R9Substituted C1-5Alkoxy, by 0~3 R9Substituted C2-6Alkenyl, by 0~3 R9Substituted C2-6Alkynes Base, by 0~3 R9Substituted aryl, by 0~3 R9Substituted heteroaryl, by 0~3 R9Substituted saturated heterocyclyl, by 0 ~3 R9Substituted saturated cyclic alkyls, by 0~3 R9Substituted condensed ring；R9Selected from halogen, cyano, hydroxyl, carboxyl ,-NH2、- NO2、C1-5Alkoxy, C1-5Alkyl；
Above-mentioned X is selected from nothing, R6、-R6COR7-、-R6OR7-、-R6SR7-、-R6OC(O)R7-、-R6C(O)OR7、-R6NHR7-、- R6CONHR7-、-R6NHCOR7-、-R6SO2R7, wherein R6、R7It is each independently selected from nothing, C1-5Alkylidene, C2-6Alkenylene, C2-6 Alkynylene；
R5Selected from-SR8, hydrogen, halogen, cyano, hydroxyl, carboxyl ,-NH2、-NO2、C1-5Alkyl, C1-5Alkoxy, C2-6Alkenyl, C2-6Alkynyl；R8Selected from C1-5Alkyl.
Further, the structure of the compound is as shown in Formula II:
Wherein, R1Selected from hydroxyl, C1-3Alkoxy, C1-3Alkyl；
R3、R4It is each independently selected from H, halogen, C1-3Alkyl, C1-3Alkoxy；
X is selected from-R6COR7, wherein R6、R7It is each independently selected from nothing, C1-3Alkylidene, C2-4Alkenylene, C2-4Alkynylene；
R5Selected from-SR8, hydrogen, halogen, cyano, hydroxyl, carboxyl ,-NH2、-NO2、C1-3Alkyl, C1-3Alkoxy, C2-4Alkenyl, C2-4Alkynyl；R8Selected from methyl.
Further, the structure of the compound are as follows:
。
The present invention also provides it is above-mentioned be III compound preparation method, the preparation method comprises the following steps:
(1) reducing agent is added into 5- bromindion, reacts, obtains intermediate 1；
(2) catalyst, n,N-dimethylacetamide are sequentially added into intermediate 1, are reacted, are obtained intermediate 2；
(3) intermediate 2 is reacted with bromoacetate, obtains intermediate 3；
(4) with to methylthio phenyl formaldehyde aldol reaction occurs for intermediate 3, obtains intermediate 4；
(5) intermediate 4 is reacted with sodium hydroxide, obtains compound shown in formula III；
Wherein, the structure of the intermediate 1 isThe structure of intermediate 2 isIn The structure of mesosome 3 isThe structure of intermediate 4 is
Further, in step (1), the reducing agent is selected from sodium borohydride；Mole of the 5- bromindion and reducing agent Than for 1:(0.8~1.2)；The temperature of the reaction is room temperature, and the time is 1~3 hour；The solvent of reaction is organic solvent；Add Enter reducing agent before controlled at 0~10 DEG C；
And/or in step (2), the catalyst is selected from n-BuLi；The reaction condition are as follows: be added catalyst after- It reacts 0.5~2 hour at 60~-80 DEG C, is reacted at room temperature 1~3 hour after n,N-dimethylacetamide is added；Intermediate 1, Catalyst, DMAC N,N' dimethyl acetamide molar ratio be 1:(2~3): (1.5~2.5)；The solvent of reaction is organic solvent；
And/or in step (3), the reaction is carried out in the presence of Anhydrous potassium carbonate, intermediate 2, Carbon Dioxide Potassium, bromoacetate molar ratio be 1:(1~3): (1~2)；The reaction temperature be heated to reflux, the reaction time be 12~ 36 hours；The solvent of reaction is organic solvent；
And/or in step (4), the intermediate 3 is 1:(0.8~1.2 to the molar ratio of methylthio phenyl formaldehyde)；Reaction Temperature is room temperature, and the reaction time is 12~36 hours；The solvent of reaction is the ethanol solution of hydrogen chloride；
And/or in step (5), the intermediate 4, sodium hydroxide molar ratio be 1:(2~5)；Reaction temperature be 25~ 50 DEG C, the reaction time is 4~8 hours；Reaction dissolvent is the mixed solution of methanol and water.
Further, in step (1), the molar ratio of the 5- bromindion and reducing agent is 1:1；The temperature of the reaction is Room temperature, time are 2 hours；The solvent of reaction is methanol；It is added before reducing agent controlled at 0~5 DEG C；
And/or in step (2), the catalyst is selected from n-BuLi；The reaction condition are as follows: be added -70 after catalyst DEG C reaction 1 hour, be added n,N-dimethylacetamide after react at room temperature 2 hours；Intermediate 1, catalyst, N, N- dimethylacetamide The molar ratio of amine is 1:2.5:2；The solvent of reaction is tetrahydrofuran；
And/or in step (3), the reaction is carried out in the presence of Anhydrous potassium carbonate, intermediate 2, Carbon Dioxide Potassium, bromoacetate molar ratio be 1:2:1.5；The reaction temperature is to be heated to reflux, and the reaction time is 24 hours；Reaction Solvent is acetonitrile；
And/or in step (4), the intermediate 3 is 1:1 to the molar ratio of methylthio phenyl formaldehyde；Reaction temperature is room Temperature, reaction time are 24 hours；
And/or in step (5), the intermediate 4, sodium hydroxide molar ratio be 1:3；Reaction temperature is 40 DEG C, reaction Time is 6 hours；Reaction dissolvent is the mixed solution that the volume ratio of methanol and water is 1:1.
The present invention also provides compound shown in above-mentioned Formulas I~III or its conformer or its optical isomer or Its pharmaceutically acceptable salt or its pharmaceutically acceptable salt or its prodrug or its hydrate or its solvate conduct The purposes of peroxisome proliferation-activated receptors agonist；
Preferably, the peroxisome proliferation-activated receptors are α and/or δ receptor.
Further, the peroxisome proliferation-activated receptors agonist is to prevent and/or treat following disease Drug: lipid and/or abnormal carbohydrate metabolism related disease, liver related disease, transaminase blood plasma level exception related disease；
Preferably, the disease be selected from dyslipidemia, Cardiovascular abnormality, diabetes, obesity, nonalcoholic fatty liver, Nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma.
The present invention also provides a kind of pharmaceutical composition, described pharmaceutical composition is with chemical combination shown in above-mentioned Formulas I~III Object or its conformer or its optical isomer or its pharmaceutically acceptable salt or its pharmaceutically acceptable salt or Its prodrug or its hydrate or its solvate are active constituent, in addition what pharmaceutically acceptable auxiliary material was prepared.
Further, described pharmaceutical composition is oral preparation.
It is experimentally confirmed, the compounds of this invention has higher agonist activity to PPAR α, γ or δ, may be used as PPAR Agonist；In addition, the compounds of this invention pair a variety of biochemical parameters relevant to liver disorders include triglycerides, cholesterol Deng have significant front regulating effect, to prepare lipid and/or abnormal carbohydrate metabolism related disease, liver related disease, turning ammonia The drug of the blood plasma level exception related disease of enzyme provides new selection." substitution " refer to the hydrogen atom in molecule by it is other not Same atom or molecule is replaced.
The minimum value and maximum value of carbon content are indicated by prefix in hydrocarbon group, for example, C1-5 alkyl shows to appoint What alkyl containing 1-5 carbon atom.
" alkylidene " refers to that alkane loses remaining group after two hydrogen atoms, likewise, " alkenylene " refers to that alkene loses Remove remaining group after two hydrogen atoms；" alkynylene " refers to that alkynes loses remaining group after two hydrogen atoms.For example, C2 is sub- Alkenyl indicate structure be
"-SO2- " indicate structure be
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
Below by way of specific embodiment, above content of the invention is described in further detail again.But it should not incite somebody to action This range for being interpreted as the above-mentioned theme of the present invention is only limitted to example below.All technologies realized based on above content of the present invention It all belongs to the scope of the present invention.
Specific embodiment
The raw materials used in the present invention and reagent are known product, as obtained by purchase commercial product.
The preparation of embodiment 1, the compounds of this invention (A Lai Nore)
The synthesis of the bromo- 2,3- dihydro -1H-1- indanol (intermediate 1) of step 1:5-
5- bromindion (30g, 142.2mmol) is added in 500 milliliters of reaction flasks, 150 ml methanols, ice-water bath is cooled to 0 ~5 DEG C, sodium borohydride (5.4g, 142.2mmol) is added in batches in stirring, finishes and reaction 2 hours is stirred at room temperature.TLC monitoring is anti- Reaction solution should be slowly poured into ice water completely, ethyl acetate extraction separates organic layer, saturated common salt water washing, anhydrous slufuric acid Sodium is dry, and concentration obtains bromo- 2, the 3- dihydro -1H-1- indanol (intermediate 1) of 5-, weighs 24.5 grams, yield 81%.
1H NMR(400MHz,CD3SOCD3)δ7.37(m,2H),7.12(s,1H),4.64(m,1H),2.82-2.31(m, 2H), 2.31 (m, 1H), 2.08 (m, 1H) .ESIMS m/z=214.9 (M+1)
The synthesis of step 2:5- acetyl group -2,3- dihydro -1H-1- indanol (intermediate 2)
Intermediate 1 (20 grams, 93.9mmol) are added in 500 milliliters of reaction flasks, 200 milliliters of anhydrous tetrahydro furans, the dry ice bath - 70 DEG C are cooled to, the hexane solution (94 milliliters, 234.7mol) of the n-BuLi of agitation and dropping 2.5N, drop finishes -70 DEG C of stirrings Reaction 1 hour, is added dropwise the tetrahydrofuran solution of n,N-dimethylacetamide (16 grams, 187.8mmol), and drop finishes, is gradually heated to Room temperature is stirred to react 2 hours.Reaction solution is poured into ice water, ethyl acetate extraction, saturated common salt water washing, and anhydrous sodium sulfate is dry It is dry, it is concentrated to give brown oil liquid, column chromatographs (ethyl acetate: petroleum ether=1:1) purifying, obtains white solid product, weigh 8.8 Gram.Yield 54%.
1H NMR(400MHz,CD3SOCD3)δ7.77(m,2H),7.22(s,1H),4.54(m,1H),2.79-2.31(m, 4H), 2.29 (m, 1H), 2.02 (m, 1H) .ESIMS m/z=177.1 (M+1)
The synthesis of step 3:5- acetyl group -2,3- dihydro -1H-1- indenes fluoroacetic acid ethyl ester (intermediate 3)
Intermediate 2 (5 grams, 28.4mmol) are added in 100 milliliters of reaction flasks, Anhydrous potassium carbonate (7.8 grams of 56.8mmol), second 40 milliliters of nitrile, bromoacetate (7.1 grams, 42.6mmol) is heated to flowing back, be stirred to react 24 hours, and TLC is shown among raw material Body 2 disappears.
Stop reaction, be filtered to remove potassium carbonate, filtrate concentration, column chromatographs (ethyl acetate: petroleum ether=1:10), obtains white Solid product intermediate 3 weighs 5.4 grams, yield 72%.
1H NMR(400MHz,CD3SOCD3)δ7.74(m,2H),7.29(s,1H),4.36(m,3H),4.12(m,2H) 2.79-2.31 (m, 4H), 2.29 (m, 1H), 2.02 (m, 1H), 1.25 (m, 3H) .ESIMS m/z=263.1 (M+1)
Step 4:(E) -5- (3- (4- methyl mercapto phenyl) acryloyl group) -2,3- dihydro -1H-1- indenes fluoroacetic acid ethyl ester (in Mesosome 4) synthesis
In 100 milliliters of reaction flasks be added intermediate 3 (5 grams, 19.1mmol), to methylthio phenyl formaldehyde (2.9 grams, 19.1mmol), reaction 24 hours is stirred at room temperature in molten 20 milliliters of the ethyl alcohol of hydrogen chloride, and solid product is precipitated, and ice-water bath is cooled to 0 It~5 DEG C, stirs 2 hours, filtering, 40 DEG C of obtained solid are dried under reduced pressure, and obtain intermediate 4, weigh 5.5 grams, yield 73%.
1H NMR(400MHz,CD3SOCD3)δ8.08(d,1H),7.71(m,2H),7.57(d,1H),7.21-7.40(m, 5H), 4.33 (s, 2H), 4.21 (m, 2H), 3.98 (t, 2H), 2.51-2.90 (m, 6H), 1.21 (t, 3H) .ESIMS m/z= 397.5(M+1).
Step 5:(E) -5- (3- (4- methyl mercapto phenyl) acryloyl group) -2,3- dihydro -1H-1- indenes fluoroacetic acid (A Lainuo You) synthesis
Intermediate 4 (5 grams, 12.6mmol) are added in 100 milliliters of reaction flasks, sodium hydroxide (1.5 grams, 37.8mmol), 5 millis Water is risen, 5 ml methanols are heated to 40 DEG C, are stirred to react 6 hours, dilute hydrochloric acid tune PH to 2, and solid is precipitated, and solid is collected in filtering, 50 DEG C are dried under reduced pressure, and obtain product, are named as A Lai Nore, weigh 2.7 grams, purity 99.72%, yield 58%.
1H NMR(400MHz,CD3SOCD3)δ7.98(d,1H),7.76(m,2H),7.52(d,1H),7.17-7.33(m, 5H), 4.31 (s, 2H), 4.15 (m, 2H), 2.41-2.87 (m, 6H) .ESIMS m/z=369.1 (M+1)
Beneficial effects of the present invention are proved below by way of experimental example.
Experimental example 1, the compounds of this invention test the agonist activity of PPAR α, γ or δ
1, experimental method
By detection luciferase activity come evaluate the embodiment of the present invention 1 preparation compound (A Lai Nore) to PPAR by The agonist activity of body.
The transfection measuring method of PPAR receptor: HEK293 cell is being supplemented into 10%FBS and glutamine (GIBCOBRL) it is cultivated in DMEM/F-12 culture medium.Using DMRIE-C reagent, by cell PPAR-Gal4 (PPAR α, γ Or δ) receptor dna and Gal4- luciferase reporter gene cotransfection.Culture medium is changed to what 5% active carbon came out by next day FBS growth medium.It is cells trypsinised and be inoculated on 96 orifice plates with the density of 50000 cells/wells after 6 hours, In 73 DEG C/5%CO2It is incubated for 24 hours in incubator.It is surveyed with Steady-Glo luciferase magnetic nail kit (coming from Promega) Determine luciferase activity.
Wherein, DMRIE-C reagent is purchased from GIBCO, catalog number 10459-014；The low blood serum medium purchase of OPTI-MEMI From GIBCOBRL, catalog number 31985；Steady-Glo luciferase assay kit is purchased from Promega Part# E254B。
2, experimental result
The compound A Lai Nore prepared using the above method detection embodiment of the present invention 1 is living to PPAR α, γ or δ excitement Property.Half effective concentration (EC50) value is as shown in table 1.
1. A Lai Nore of table is to PPAR α, γ or δ agonist activity data
Target spot EC50(nmol)
PPARα 0.5
PPARγ 1.3
PPARδ 0.8
As can be seen from the above table, the compounds of this invention has a higher agonist activity to PPAR α, γ or δ, especially pair It is obviously living with high excitement to illustrate that the compounds of this invention has PPAR α, δ down to 0.5~0.8nmol by PPAR α, δ, EC50 Property.
So the compounds of this invention may be used as PPAR agonist, especially PPAR α, PPAR delta agonists.
The influence of experimental example 2, the compounds of this invention (A Lai Nore) to Serum Lipids in Experimental HypercholesterolemicRats
1, experimental method
1.1 drugs:
Compound (E) -5- (3- (4- methyl mercapto phenyl) acryloyl group) -2,3- dihydro-prepared by this law embodiment 1 1H-1- indenes fluoroacetic acid (A Lai Nore) is configured to the hard-shell capsule containing 50mg compound；And (starch is purchased from lake by placebo Nan Erkang Pharmacy stock Co., Ltd) as control.
1.2 experimental animals and grouping:
Wistar rat (second level), male, weight 160-170g.In 25 DEG C of room temperature, humidity 30%~40%, adaptability is raised After supporting 1 week, 25 grams of high fat diet are quantitatively given daily, until the 26th day builds up Arteriosclerosis rat model.According to rat triglycerides Level is divided into two groups, every group of 10 rats.Groups of animals free water, daily administration in afternoon A Lai Nore (50mg) and placebo After (50mg) 30 minutes, every animal quantitatively gives 25 grams of feed, tests 10 days.
1.3 data processings:
Blood lipid is indicated with x ± s, is made variance analysis with SAS software package, is examined the conspicuousness of difference.
2, experimental result
The influence of 2.1 pairs of hyperlipemia rat triglycerides
A Lai Nore 50mg/kg group, compared with placebo, Triglycerides in Serum level reduces (P < 0.01).Experiment As a result as shown in table 2-1 and 2-2.
Table 2-1 takes placebo rat triglyceride concentration
Table 2-2 takes A Lai Nore group rat triglyceride concentration
The influence of 2.2 pairs of rat total cholesterols
Total cholesterol level is lower than the rat (P < 0.01) of placebo in the rat blood serum of A Lai Nore 50mg/kg group. Experimental result is as shown in following table 2-3 and 2-4.
Table 2-3 takes placebo rat total cholesterol concentration
Table 2-4 takes A Lai Nore group rat total cholesterol concentration
To sum up, the present invention provides a kind of Formulas I compounds represented, have higher excitement living PPAR α, γ or δ Property, it may be used as PPAR agonist；In addition, the compounds of this invention pair a variety of biochemical parameters relevant to liver disorders include Triglycerides, cholesterol etc. have significant front regulating effect, to prepare lipid and/or abnormal carbohydrate metabolism related disease, liver Dirty related disease, the blood plasma level exception related disease of transaminase drug provide new selection.

Claims (10)

1. compound shown in Formulas I or its conformer or its optical isomer or its pharmaceutically acceptable salt or its medicine Acceptable salt or its prodrug or its hydrate or its solvate on:
Wherein, R1Selected from hydroxyl, C1-5Alkoxy, C1-5Alkyl；
R3、R4It is each independently selected from H, halogen, C1-5Alkyl, C1-5Alkoxy；
R2Selected from hydrogen, halogen, cyano, hydroxyl, carboxyl ,-NH2、-NO2、By 0~3 R9Substituted C1-5Alkane Base, by 0~3 R9Substituted C1-5Alkoxy, by 0~3 R9Substituted C2-6Alkenyl, by 0~3 R9Substituted C2-6Alkynyl, By 0~3 R9Substituted aryl, by 0~3 R9Substituted heteroaryl, by 0~3 R9Substituted saturated heterocyclyl, by 0~3 A R9Substituted saturated cyclic alkyls, by 0~3 R9Substituted condensed ring；R9Selected from halogen, cyano, hydroxyl, carboxyl ,-NH2、-NO2、 C1-5Alkoxy, C1-5Alkyl；
Above-mentioned X is selected from nothing, R6、-R6COR7-、-R6OR7-、-R6SR7-、-R6OC(O)R7-、-R6C(O)OR7、-R6NHR7-、- R6CONHR7-、-R6NHCOR7-、-R6SO2R7, wherein R6、R7It is each independently selected from nothing, C1-5Alkylidene, C2-6Alkenylene, C2-6 Alkynylene；
R5Selected from-SR8, hydrogen, halogen, cyano, hydroxyl, carboxyl ,-NH2、-NO2、C1-5Alkyl, C1-5Alkoxy, C2-6Alkenyl, C2-6Alkynes Base；R8Selected from C1-5Alkyl.
2. compound according to claim 1 or its conformer or its optical isomer or its can pharmaceutically connect The salt received or its pharmaceutically acceptable salt or its prodrug or its hydrate or its solvate, it is characterised in that: described The structure of compound is as shown in Formula II:
Wherein, R1Selected from hydroxyl, C1-3Alkoxy, C1-3Alkyl；
R3、R4It is each independently selected from H, halogen, C1-3Alkyl, C1-3Alkoxy；
X is selected from-R6COR7, wherein R6、R7It is each independently selected from nothing, C1-3Alkylidene, C2-4Alkenylene, C2-4Alkynylene；
R5Selected from-SR8, hydrogen, halogen, cyano, hydroxyl, carboxyl ,-NH2、-NO2、C1-3Alkyl, C1-3Alkoxy, C2-4Alkenyl, C2-4Alkynes Base；R8Selected from methyl.
3. compound according to claim 1 or its conformer or its optical isomer or its can pharmaceutically connect The salt received or its pharmaceutically acceptable salt or its prodrug or its hydrate or its solvate, it is characterised in that: described The structure of compound are as follows:
。
4. a kind of preparation method of compound described in claim 3, it is characterised in that: the preparation method comprises the following steps:
(1) reducing agent is added into 5- bromindion, reacts, obtains intermediate 1；
(2) catalyst, n,N-dimethylacetamide are sequentially added into intermediate 1, are reacted, are obtained intermediate 2；
(3) intermediate 2 is reacted with bromoacetate, obtains intermediate 3；
(4) with to methylthio phenyl formaldehyde aldol reaction occurs for intermediate 3, obtains intermediate 4；
(5) intermediate 4 is reacted with sodium hydroxide, obtains compound described in claim 3；
Wherein, the structure of the intermediate 1 isThe structure of intermediate 2 isIntermediate 3 Structure beThe structure of intermediate 4 is
5. the preparation method according to claim 4, it is characterised in that: in step (1), the reducing agent is selected from hydroboration Sodium；The molar ratio of the 5- bromindion and reducing agent is 1:(0.8~1.2)；The temperature of the reaction is room temperature, and the time is 1~3 Hour；The solvent of reaction is organic solvent；It is added before reducing agent controlled at 0~10 DEG C；
And/or in step (2), the catalyst is selected from n-BuLi；The reaction condition are as follows: be added after catalyst -60 It reacts 0.5~2 hour at~-80 DEG C, is reacted at room temperature 1~3 hour after n,N-dimethylacetamide is added；Intermediate 1 is urged Agent, the molar ratio of DMAC N,N' dimethyl acetamide are 1:(2~3): (1.5~2.5)；The solvent of reaction is organic solvent；
And/or in step (3), the reaction is carried out in the presence of Anhydrous potassium carbonate, intermediate 2, Anhydrous potassium carbonate, bromine The molar ratio of ethyl acetate is 1:(1~3): (1~2)；The reaction temperature is to be heated to reflux, and the reaction time is 12~36 small When；The solvent of reaction is organic solvent；
And/or in step (4), the intermediate 3 is 1:(0.8~1.2 to the molar ratio of methylthio phenyl formaldehyde)；Reaction temperature For room temperature, the reaction time is 12~36 hours；The solvent of reaction is the ethanol solution of hydrogen chloride；
And/or in step (5), the intermediate 4, sodium hydroxide molar ratio be 1:(2~5)；Reaction temperature is 25~50 DEG C, the reaction time is 4~8 hours；Reaction dissolvent is the mixed solution of methanol and water.
6. preparation method according to claim 5, it is characterised in that: in step (1), the 5- bromindion and reducing agent Molar ratio is 1:1；The temperature of the reaction is room temperature, and the time is 2 hours；The solvent of reaction is methanol；It is added before reducing agent Controlled at 0~5 DEG C；
And/or in step (2), the catalyst is selected from n-BuLi；The reaction condition are as follows: be added after catalyst -70 DEG C it is anti- It answers 1 hour, is reacted at room temperature 2 hours after n,N-dimethylacetamide is added；Intermediate 1, catalyst, DMAC N,N' dimethyl acetamide Molar ratio is 1:2.5:2；The solvent of reaction is tetrahydrofuran；
And/or in step (3), the reaction is carried out in the presence of Anhydrous potassium carbonate, intermediate 2, Anhydrous potassium carbonate, bromine The molar ratio of ethyl acetate is 1:2:1.5；The reaction temperature is to be heated to reflux, and the reaction time is 24 hours；The solvent of reaction For acetonitrile；
And/or in step (4), the intermediate 3 is 1:1 to the molar ratio of methylthio phenyl formaldehyde；Reaction temperature is room temperature, instead It is 24 hours between seasonable；
And/or in step (5), the intermediate 4, sodium hydroxide molar ratio be 1:3；Reaction temperature is 40 DEG C, the reaction time It is 6 hours；Reaction dissolvent is the mixed solution that the volume ratio of methanol and water is 1:1.
7. any one of the claim 1-3 compound or its conformer or its optical isomer or its pharmaceutically may be used The salt of receiving or its pharmaceutically acceptable salt or its prodrug or its hydrate or its solvate are as peroxidase The purposes of body proliferator activated receptor agonist；
Preferably, the peroxisome proliferation-activated receptors are α and/or δ receptor.
8. purposes according to claim 7, it is characterised in that: the peroxisome proliferation-activated receptors agonist For the drug for preventing and/or treating following disease: lipid and/or abnormal carbohydrate metabolism related disease, liver related disease, transaminase Blood plasma level exception related disease；
Preferably, the disease is selected from dyslipidemia, Cardiovascular abnormality, diabetes, obesity, nonalcoholic fatty liver, non-wine Essence fat hepatitis, cirrhosis, hepatocellular carcinoma.
9. a kind of pharmaceutical composition, it is characterised in that: described pharmaceutical composition be with compound described in claim 1-3 or Its conformer or its optical isomer or its pharmaceutically acceptable salt or its pharmaceutically acceptable salt or its before Medicine or its hydrate or its solvate are active constituent, in addition what pharmaceutically acceptable auxiliary material was prepared.
10. pharmaceutical composition according to claim 9, it is characterised in that: described pharmaceutical composition is oral preparation.
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